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PubMedDate not supplied

Kinetic chain lengths in highly cross-linked networks formed by the photoinitiated polymerization of divinyl monomers: a gel permeation chromatography investigation.

Highly cross-linked networks formed by the photoinitiated polymerization of multifunctional monomers are finding application in the field of biomaterials because of their chemical versatility, reaction control, and ability to polymerize under physiological conditions. Typically, degradation is introduced into these networks via the cross-links and leads to the release of nondegradable but water-soluble kinetic chains formed during the chain polymerization process. In this study, gel permeation chromatography (GPC) was used to characterize kinetic chain length distributions in highly cross-linked systems that are being developed for orthopedic applications. By polymerizing divinyl monomers to various conversions and subsequently degrading them, we investigated the aspects of network structural evolution related to kinetic chain formation. In general, the average kinetic chain length increased with conversion until the onset of autodeceleration, when the kinetic chains decreased in length as the propagation reaction became diffusion-controlled. The distribution of kinetic chains also changed when different initiation conditions (i.e., initiator concentration and incident light intensity) were used, and a decrease in the kinetic chain lengths was observed at higher initiation rates. Finally, kinetic chain lengths were examined as a function of depth in thick samples polymerized with different light intensities and with a photobleaching initiator. Light attenuation through the sample led to different initiation rates as a function of depth and, consequently, spatial heterogeneity in the network structure as measured by the distributions of kinetic chains.

Butadienes↗
PubMed1999

Testosterone stimulation of the medial preoptic area and medial amygdala in the control of male hamster sexual behavior: redundancy without amplification.

Receptors for gonadal steroids are present in an interconnected network of limbic nuclei. The existence of this network structure has important implications for how steroids control reproductive physiology and behavior. In 1986, Cottingham and Pfaff proposed that properties of a steroid-responsive neural network could include redundancy, amplification, stability and selective filtering. The present study tested the concept of steroid amplification, using male hamster sexual behavior as a model. In the male hamster, the medial amygdaloid nucleus (Me) and medial preoptic area (MPOA) are essential for mating behavior, and both nuclei transduce steroid cues to facilitate copulation. To determine if steroid action at multiple interconnected nuclei amplifies mating, the present study compared sexual behavior in castrated male hamsters bearing unilateral intracranial implants of testosterone in Me or MPOA with that of males with dual testosterone implants in Me and MPOA. Implants that stimulated androgen receptor-containing neurons in Me or MPOA stimulated copulatory behavior above castrate levels. However, behavior of males with dual implants was not significantly different from that of males with single implants. This suggests that steroid action at either MPOA or Me is sufficient to facilitate mating, but dual stimulation of these reciprocally-connected nuclei does not amplify sexual behavior.

Amygdala↗
PubMed1995

Pruning of rat cortical taste neurons by an artificial neural network model.

1. Taste qualities are believed to be coded in the activity of ensembles of taste neurons. However, it is not clear whether all neurons are equally responsible for coding. To clarify the point, the relative contribution of each taste neuron to coding needs to be assessed. 2. We constructed simple three-layer neural networks with input units representing cortical taste neurons of the rat. The networks were trained by the back-propagation learning algorithm to classify the neural response patterns to the basic taste stimuli (sucrose, HCl, quinine hydrochloride, and NaCl). The networks had four output units representing the basic taste qualities, the values of which provide a measure for similarity of test stimuli (salts, tartaric acid, and umami substances) to the basic taste stimuli. 3. Trained networks discriminated the response patterns to the test stimuli in a plausible manner in light of previous physiological and psychological experiments. Profiles of output values of the networks paralleled those of across-neuron correlations with respect to the highest or second-highest values in the profiles. 4. We evaluated relative contributions of input units to the taste discrimination of the network by examining their significance Sj, which is defined as the sum of the absolute values of the connection weights from the jth input unit to the hidden layer. When the input units with weaker connection weights (e.g., 15 of 39 input units) were "pruned" from the trained network, the ability of the network to discriminate the basic taste qualities as well as other test stimuli was not greatly affected. On the other hand, the taste discrimination of the network progressively deteriorated much more rapidly with pruning of input units with stronger connection weights. 5. These results suggest that cortical taste neurons differentially contribute to the coding of taste qualities. The pruning technique may enable the evaluation of a given taste neuron in terms of its relative contribution to the coding, with Sj providing a quantitative measure for such evaluation.

Animals↗
PubMed2007

Gates and oscillators II: zeitgebers and the network model of the brain clock.

Circadian rhythms in physiology and behavior are regulated by the SCN. When assessed by expression of clock genes, at least 2 distinct functional cell types are discernible within the SCN: nonrhythmic, light-inducible, retinorecipient cells and rhythmic autonomous oscillator cells that are not directly retinorecipient. To predict the responses of the circadian system, the authors have proposed a model based on these biological properties. In this model, output of rhythmic oscillator cells regulates the activity of the gate cells. The gate cells provide a daily organizing signal that maintains phase coherence among the oscillator cells. In the absence of external stimuli, this arrangement yields a multicomponent system capable of producing a self-sustained consensus rhythm. This follow-up study considers how the system responds when the gate cells are activated by an external stimulus, simulating a response to an entraining (or phase-setting) signal. In this model, the authors find that the system can be entrained to periods within the circadian range, that the free-running system can be phase shifted by timed activation of the gate, and that the phase response curve for activation is similar to that observed when animals are exposed to a light pulse. Finally, exogenous triggering of the gate over a number of days can organize an arrhythmic system, simulating the light-dependent reappearance of rhythmicity in a population of disorganized, independent oscillators. The model demonstrates that a single mechanism (i.e., the output of gate cells) can account for not only free-running and entrained rhythmicity but also other circadian phenomena, including limits of entrainment, a PRC with both delay and advance zones, and the light-dependent reappearance of rhythmicity in an arrhythmic animal.

Biological Clocks↗
PubMed1976

Ultrastructural basis for alveolar-capillary permeability to protein.

The intravenous injection into mice of small volumes (less than 0.1 ml) of peroxidatic enzymes of molecular weight of 40 000 daltons or greater results in little if any penetration of these probe molecules into endothelial junctions. The injection of cytochrome c (12 000 daltons), on the other hand, results in the localization of this tracer in some but not all endothelial junctions. When horseradish peroxidase (EC 1.11.1.7) is injected in a large volume of saline (0.5 ml), reaction product is present in endothelial junctions and basement membrane, but is prevented from entering the alveolar space by zonulae occludentes between epithelial cells. These experiments indicate that although endothelial junctions, under physiological conditions, are largely impermeable to molecules the size of horseradish peroxidase, and presumably most serum proteins, they are labile and susceptible to stretching if intravascular pressure is increased. Freeze-fracture studies show that pulmonary capillary endothelial junctions are composed of one or at the most two strands which show areas of discontinuity. Epithelial junctions, by contrast, are composed of a continuous, complex network of anastomosing fibres. These observations confirm physiological experiments which indicate that it is the pulmonary epithelium rather than the endothelium which determines the permeability properties of the alveolar-capillary membrane to lipid-insoluble molecules. Bidirectional pinocytic transport is an additional mechanism whereby lipid-insoluble molecules are transported across both endothelial and epithelial layers. The relative contribution of this transport mechanism to the total amount transported remains to be established.

Animals↗
PubMed2005

Modular analysis of the transcriptional regulatory network of E. coli.

The transcriptional network of Escherichia coli is currently the best-understood regulatory network of a single cell. Motivated by statistical evidence, suggesting a hierarchical modular architecture in this network, we identified eight modules with well-defined physiological functions. These modules were identified by a clustering approach, using the shortest path to trace regulatory relationships across genes in the network. We report the type (feed forward and bifan) and distribution of motifs between and within modules. Feed-forward motifs tend to be embedded within modules, whereas bi-fan motifs tend to link modules, supporting the notion of a hierarchical network with defined functional modules.

Escherichia coli↗
PubMed1994

Complexity, chaos and human physiology: the justification for non-linear neural computational analysis.

Background is presented to suggest that a great many biologic processes are chaotic. It is well known that chaotic processes can be accurately characterized by non-linear technologies. Evidence is presented that an artificial neural network, which is a known method for the application of non-linear statistics, is able to perform more accurately in identifying patients with and without myocardial infarction than either physicians or other computer paradigms. It is suggested that the improved performance may be due to the network's better ability to characterize what is a chaotic process imbedded in the problem of the clinical diagnosis of this entity.

Diagnosis, Computer-Assisted↗
PubMed2003

Interactive instruction of cellular physiology for remote learning.

The biomedical sciences are a rapidly changing discipline that have adapted to innovative technological advances. Despite these many advances, we face two major challenges: a) the number of experts in the field is vastly outnumbered by the number of students, many of whom are separated geographically or temporally and b) the teaching methods used to instruct students and learners have not changed. Today's students have adapted to technology--they use the web as a source of information and communicate via email and chat rooms. Teaching in the biomedical sciences should adopt these new information technologies (IT), but has thus far failed to capitalize on technological opportunity. Creating a "digital textbook" of the traditional learning material is not sufficient for dynamic processes such as cellular physiology. This paper describes innovative teaching techniques that incorporate familiar IT and high-quality interactive learning content with user-centric instruction design models. The Virtual Labs Project from Stanford University has created effective interactive online teaching modules in physiology (simPHYSIO) and delivered them over broadband networks to their undergraduate and medical students. Evaluation results of the modules are given as a measure of success of such innovative teaching method. This learning media strategically merges IT innovations with pedagogy to produce user-driven animations of processes and engaging interactive simulations.

Biology↗
PubMed2002

Recovery of locomotion in the cat following spinal cord lesions.

In most species, locomotor function beneath the level of a spinal cord lesion can be restored even if the cord is completely transected. This suggests that there is, within the spinal cord, an autonomous network of neurons capable of generating a locomotor pattern independently of supraspinal inputs. Recent studies suggest that several physiological and neurochemical changes have to occur in the neuronal networks located caudally to the lesion to allow the expression of spinal locomotion. Some evidence of this plasticity will be addressed in this review. In addition, original data on the functional organisation of the lumbar spinal cord will also be presented. Recent works in our lab show that segmental responsiveness of the spinal cord of the cat to locally micro-injected drugs in different lumbar segments, in combination with complete lesions at various level of the spinal cord, suggest a rostro-caudal organisation of spinal locomotor control. Moreover, the integrity of midlumbar segments seems to be crucial for the expression of spinal locomotion. These data suggest that the regions of critical importance for locomotion can be confined to a restricted portion of the spinal cord. Later, these midlumbar segments could be targeted by electrical stimulation or grafts to improve recovery of function. Understanding the changes in spinal cord neurophysiology and neurochemistry after a lesion is of critical importance to the improvement of treatments for locomotor rehabilitation in spinal-cord-injured patients.

Animals↗
PubMed2005

The multifarious short-term regulation of ammonium assimilation of Escherichia coli: dissection using an in silico replica.

Ammonium assimilation in Escherichia coli is regulated through multiple mechanisms (metabolic, signal transduction leading to covalent modification, transcription, and translation), which (in-)directly affect the activities of its two ammonium-assimilating enzymes, i.e. glutamine synthetase (GS) and glutamate dehydrogenase (GDH). Much is known about the kinetic properties of the components of the regulatory network that these enzymes are part of, but the ways in which, and the extents to which the network leads to subtle and quasi-intelligent regulation are unappreciated. To determine whether our present knowledge of the interactions between and the kinetic properties of the components of this network is complete - to the extent that when integrated in a kinetic model it suffices to calculate observed physiological behaviour - we now construct a kinetic model of this network, based on all of the kinetic data on the components that is available in the literature. We use this model to analyse regulation of ammonium assimilation at various carbon statuses for cells that have adapted to low and high ammonium concentrations. We show how a sudden increase in ammonium availability brings about a rapid redirection of the ammonium assimilation flux from GS/glutamate synthase (GOGAT) to GDH. The extent of redistribution depends on the nitrogen and carbon status of the cell. We develop a method to quantify the relative importance of the various regulators in the network. We find the importance is shared among regulators. We confirm that the adenylylation state of GS is the major regulator but that a total of 40% of the regulation is mediated by ADP (22%), glutamate (10%), glutamine (7%) and ATP (1%). The total steady-state ammonium assimilation flux is remarkably robust against changes in the ammonium concentration, but the fluxes through GS and GDH are completely nonrobust. Gene expression of GOGAT above a threshold value makes expression of GS under ammonium-limited conditions, and of GDH under glucose-limited conditions, sufficient for ammonium assimilation.

Adenosine Diphosphate↗
PubMed2006

Experimental approaches to identify genetic networks.

Systems biology offers the promise of a fully integrated view of cellular physiology. To realize this potential requires the analysis of diverse genome-wide datasets and the incorporation of these analyses into integrated networks. In the past decade, the budding yeast Saccharomyces cerevisiae has provided the benchmark for the design of such large-scale experiments. Many of these experimental approaches have been adopted and adapted to study other systems, including worm, fly, fish and mammalian cultured cells, using an ingenious set of molecular tools.

Animals↗
PubMed1982

Microtubule complexes correlated with growth rate and water proton relaxation times in human breast cancer cells.

Ten established human breast cancer cell lines display patterns of microtubule organization which are characterized by growth rate of the cell populations and the freedom of mobility of cellular water molecules measured by nuclear magnetic resonance spectroscopy. Cell lines with population-doubling times of 1 to 2 days demonstrate rapid mobility of water molecules by proton spin-lattice and spin-spin relaxation times (T1 greater than 750 msec, T2 greater than 120 msec) and have diffuse patterns of tubulin immunofluorescent antibody staining. Moderately fast dividing cells (population-doubling times of 3 to 7 days) have T1 values of 600 to 750 msec and show approximately 50% organized complexes of polymerized microtubules in the cytoplasm. Slow-growing cell lines demonstrate more restricted mobility of water molecules (T1 values of 500 to 600 msec) and contain abundant networks of polymerized microtubules. The three-way correlation of the physical parameter of water proton relaxation times, the structural parameter of microtubule organization, and the physiological parameter of growth suggest a close interaction of water molecules with the cytoplasmic macromolecular network in the performance of physiological function.

Body Water↗
PubMed2002

The community of the self.

Good health, which reflects the harmonious integration of molecules, cells, tissues and organs, is dynamically stable: when displaced by disease, compensation and correction are common, even without medical care. Physiology and computational biology now suggest that healthy dynamic stability arises through the combination of specific feedback mechanisms and spontaneous properties of interconnected networks. Today's physicians are already testing to 'see if the network is right'; tomorrow's physicians may well use therapies to 'make the network right'.

Feedback, Physiological↗
PubMed2006

On the way to understand biological complexity in plants: S-nutrition as a case study for systems biology.

The establishment of technologies for high-throughput DNA sequencing (genomics), gene expression (transcriptomics), metabolite and ion analysis (metabolomics/ionomics) and protein analysis (proteomics) carries with it the challenge of processing and interpreting the accumulating data sets. Publicly accessible databases and newly development and adapted bioinformatic tools are employed to mine this data in order to filter relevant correlations and create models describing physiological states. These data allow the reconstruction of networks of interactions of the various cellular components as enzyme activities and complexes, gene expression, metabolite pools or pathway flux modes. Especially when merging information from transcriptomics, metabolomics and proteomics into consistent models, it will be possible to describe and predict the behaviour of biological systems, for example with respect to endogenous or environmental changes. However, to capture the interactions of network elements requires measurements under a variety of conditions to generate or refine existing models. The ultimate goal of systems biology is to understand the molecular principles governing plant responses and consistently explain plant physiology.

Arabidopsis↗
PubMed2002

Constrained synaptic connectivity in functional mammalian neuronal networks grown on patterned surfaces.

The use of ordered neuronal networks in vitro is a promising approach to study the development and the activity of small neuronal assemblies. However, in previous attempts, sufficient growth control and physiological maturation of neurons could not be achieved. Here we describe an original protocol in which polylysine patterns confine the adhesion of cellular bodies to prescribed spots and the neuritic growth to thin lines. Hippocampal neurons in these networks are maintained healthy in serum free medium up to 5 weeks in vitro. Electrophysiology and immunochemistry show that neurons exhibit mature excitatory and inhibitory synapses and calcium imaging reveals spontaneous activity of neurons in isolated networks. We demonstrate that neurons in these geometrical networks form functional synapses preferentially to their first neighbors. We have, therefore, established a simple and robust protocol to constrain both the location of neuronal cell bodies and their pattern of connectivity. Moreover, the long term maintenance of the geometry and the physiology of the networks raises the possibility of new applications for systematic screening of pharmacological agents and for electronic to neuron devices.

Action Potentials↗
PubMed2007

Molecular portrait of high productivity in recombinant NS0 cells.

Many important therapeutic proteins are produced in recombinant mammalian cells. Upon the introduction of the product gene, the isolated clones typically exhibit a wide range of productivity and high producers are subsequently selected for use in production. Using DNA microarray, two-dimensional gel electrophoresis (2DE), and iTRAQ as global surveying tools, we examined the transcriptome and proteome profiles of 11 lines of NS0 cells producing the same antibody molecule. Genes that are significantly differentially expressed between high and low producer groups statistically fall into a number of functional classes. Their distribution among the functional classes differs somewhat between transcriptomic and proteomic results. Overall, a high degree of consistency between transcriptome and proteome analysis are seen, although some genes exhibiting inconsistent trends between transcript and protein levels were observed as expected. In a novel approach, functional gene networks were retrieved using computational pathway analysis tools and their association with productivity was tested by physiological comprehension of the possible pathways involved in high recombinant protein production. Network analysis indicates that protein synthesis pathways were altered in high producers at both transcriptome and proteome levels, whereas the effect on cell growth/death pathways was more prominent only at the transcript level. The results suggest a common mechanism entailing the alteration of protein synthesis and cell growth control networks leading to high productivity. However, alternate routes with different sets of genes may be invoked to give rise to the same mechanistic outcomes. Such systematic approaches, combining transcriptomic and proteomic tools to examine high and low producers of recombinant mammalian cells will greatly enhance our capability to rationally design high producer cells. This work is a first step towards shedding a new light on the global physiological landscape of hyper productivity of recombinant cells.

Animals↗
PubMed2005

Flexible nets. The roles of intrinsic disorder in protein interaction networks.

Proteins participate in complex sets of interactions that represent the mechanistic foundation for much of the physiology and function of the cell. These protein-protein interactions are organized into exquisitely complex networks. The architecture of protein-protein interaction networks was recently proposed to be scale-free, with most of the proteins having only one or two connections but with relatively fewer 'hubs' possessing tens, hundreds or more links. The high level of hub connectivity must somehow be reflected in protein structure. What structural quality of hub proteins enables them to interact with large numbers of diverse targets? One possibility would be to employ binding regions that have the ability to bind multiple, structurally diverse partners. This trait can be imparted by the incorporation of intrinsic disorder in one or both partners. To illustrate the value of such contributions, this review examines the roles of intrinsic disorder in protein network architecture. We show that there are three general ways that intrinsic disorder can contribute: First, intrinsic disorder can serve as the structural basis for hub protein promiscuity; secondly, intrinsically disordered proteins can bind to structured hub proteins; and thirdly, intrinsic disorder can provide flexible linkers between functional domains with the linkers enabling mechanisms that facilitate binding diversity. An important research direction will be to determine what fraction of protein-protein interaction in regulatory networks relies on intrinsic disorder.

Animals↗
PubMed2000

The activity-dependent plasticity of segmental and intersegmental synaptic connections in the lamprey spinal cord.

Activity-dependent synaptic plasticity has been proposed as a contributory factor in the patterning of rhythmic network activity. However, its role has not been examined in detail. Here, paired or triple intracellular recordings have been made from identified neurons in the lamprey locomotor network to examine the potential relevance of activity-dependent synaptic plasticity in segmental and intersegmental spinal networks. Segmental inputs from glutamatergic excitatory interneurons (EIN) to ipsilateral glycinergic crossed caudal (CC) interneurons were facilitated or depressed during spike trains at 5-20 Hz. Connections between EINs were depressed. Glycinergic inputs from small ipsilateral inhibitory interneurons were depressed in motor neurons, but were facilitated in CC interneurons. Excitatory inputs from small crossing interneurons to motor neurons were depressed, whereas inhibitory inputs were unaffected. With the exception of connections between EINs, significant effects occurred with stimulation that mimicked interneuron spiking during network activity. Intersegmental EIN synaptic properties were also investigated. EIN inputs did not differ significantly when examined from zero to four segments rostral to motor neurons or CC interneurons. However, caudally located EINs evoked greater activity-dependent facilitation than did rostral EINs. Whilst the amplitude or plasticity of EIN inputs in the rostral or mid-trunk regions of the spinal cord did not differ, EINs in the caudal trunk region evoked greater facilitation. Synaptic transmission between locomotor network neurons thus exhibits activity-dependent plasticity in response to physiologically relevant stimulation. Activity-dependent plasticity could thus contribute to the patterning of the rhythmic network output.

Action Potentials↗